TWI223647B - Crystalline polymorph of aminoethylphenoxyacetic acid derivative - Google Patents

Abstract

The present invention relates to a crystalline polymorph of 2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxy-phenyl)-1-methylethyl]amino]ethyl]phenoxy]acetic acid having strong diffraction peaks (diffraction angle: 2theta ± 0.1 DEG) at 10.8, 19.1, 19.3, 19.8, 20.6 and 27.0 DEG in powder X-ray diffraction pattern, which has potent beta2- and beta3-adrenoceptor stimulating effects and is useful as an agent for relieving pain and promoting the removal of calculi in urolithiasis. For example, the crystalline polymorph can be prepared by hydrolyzing ethyl 2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]acetate phosphate by sodium hydroxide, adding an aqueous phosphoric acid solution at 40 DEG C and over, adding a mixed solvent of water and methanol or methanol to the resulting 2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]-amino]ethyl]phenoxy]acetic acid, and stirring the suspension at 40 DEG C to reflux temperature for 30 minutes to several hours.

Description

1223647

[Technical Field] The present invention relates to a crystalline polymorph of a novel amine ethylphenoxyacetamidine derivative useful as a pharmaceutical. If it is described in more detail, the present invention relates to a powerful adrenal corpse, a body stimulating effect, and a stone 3_adrenergic receptor stimulation, and can be used as a pain relief and stone elimination agent for water stone disease. Wait for the following formula

COOH-based amine ethyl 2R) -2 -Aminoyl] acetic acid) of [Background Technology]

Benzyloxyacetic acid derivative (chemical name: 2- [4- [2-[[(ls-2- (4-hydroxyphenyl) -bumethylethyl] amino] ethyl] phenoxy crystalline polymorph ( α-shaped crystal).-! 4 ″ 2 乂 [?! ',-2_hydroxy ~ 2- (4-hydroxyphenyl) + methylethyl] phenoxy] ethyl and pharmacological activity are still the inventors and others In the research group, there are different conditions in the 2- (4-hydroxyphenyl) -1methyl compound, and it cannot be the same in the crystalline polymorph, so even when the alkyl] amino group is related to its physical properties, It is known that the existing ratio of this method and production has become common, and it is known that various properties of non-acids are novel compounds not described in the literature. About this 2- [4- [2-[[(is, 2R) -2 -ethyl] amine Several types of crystalline polymorphs of ethyl] ethyl] benzyloxy] acetic acid, and the types of crystalline polymorphs obtained and the substances that obtain a certain quality according to the production. Compounds, because the same compound of each crystalline polymorph also shows complete phase

89100860.ptd $ 7 pages 1223647 V. The effect of the invention (2). Especially for medicine ^ Differences in speed, stability, etc. ^ It is known that the difference in solubility of crystalline polymorphs can be observed. Take :: Use the same-combination 4, :: Different from the predicted effect ::: The effect . The program can often be expected-the state of effect of the test. Therefore, it is necessary to use a compound having the quality of a compound in which a crystalline polymorph is present. In order to ensure that when it is a pharmaceutical product that is required as a pharmaceutical product, in order to ensure that ... it has a -determination effect, it is expected to be a stable crystal of the same quality; r and on preservation, the period 2- [4- [ 2-[[(1S, 2R) _2 Xitun body. [Amino] Ethyl] Ethyl] benzyloxy A1 r via phenyl) -1-methyl ethyl milk & "acetic acid is a number of substances, and there are mixed deposits according to the manufacturing method = ,,, or The combination of day and night shapes, and in some crystalline polymorphs, the crystalline polymorphs of the furnace two. Changed, unable to maintain a certain: ": the external environment of time changes, and-fixed and: the pharmaceutical" Nuwa's crystalline polymorphs, and established a method that can constantly maintain the body of 21 things. Pay this ,,, mouth crystal polymorphic [Disclosure of the invention]. == In the powder X-ray diffraction pattern, the diffraction angle (" Shi

Shepi Peak's novel 2_ [4_ [2 _ [[(ls, 2R) j meridian group I Luo Gongbenji)-fluorenylethyl] amino] ethyl] phenoxy body (α-shaped crystal). At the same time, the inventors are committed to reviewing the pain as a urethral calculi. 1223647 V. Description of the invention (3) Pain relief and useful stone-promoting agents 2- [4- [ A crystalline polymorph of 2-[[(1S, 2R) -2 -hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid was found The crystalline polymorph of the present invention can be manufactured with a certain quality according to the following method, and it has been found that the crystalline polymorph of the present invention is excellent in moisture resistance and the like, and is extremely useful as a medicine, and has reached the cost of the invention. The crystalline polymorph of the present invention can be used, for example, by making 2- [4— [2-[[(ls, 2R) -2 -Protyl-2- (4-transphenyl) -1 ethyl acetate phosphate, After adding hydrogen phosphoric acid aqueous solution, and filtering the 2- (4-hydroxyphenyl) -1-fluorenylethyl, add 1: 1 or methanol without drying, and save 30 minutes. For several hours, the crystal polymorph of the present invention can be diffracted outside the line according to the amount of processing and the type of solvent used, and the crystal can be displayed at a diffraction angle (2 20 · 3, 21 · 2, and 22.4 degrees). 10. 2. The crystalline polymorphs showing strong diffraction peaks are hygroscopic and easy to understand. The crystalline polymorphs are hygroscopic even in the phase, which is excellent in moisture resistance. The polymorphs are in water (37 ° C). Monomethylethyl] amino] ethyl] phenoxy] Sodium oxide is hydrolyzed to obtain 2- [4- [2- [[(1S, 2R) -2-hydroxyl]] above 40 ° C. Amine] ethyl] phenoxy] acetic acid is a mixed solvent of water and methanol (capacity ratio is suspended at 40 ° C to reflux temperature. Manufactured. Stirring temperature and stirring time can be appropriately determined based on the amount and amount etc. Determine the crystalline polymorph 'For example, in powder X-rays Θ ± 0 · 1 degree), crystalline polymorphs (α > 13 · 2, 17 · 6, 19 · 8, and 20) with strong diffraction peaks at 18 · 1, 19.7, 6-degree storage, polymorphs (6-shaped crystals), but these concerns become their hydrates. In contrast, the present invention is not stored for 10 days at a humidity of 5 1 ~ 93%. The crystalline / present resolution of the present invention is 2.7 mg / ml, which is more than

89100860.ptd Page 9 U23647 V. Description of the invention (4) -------- ---- f The solubility of f crystal 18 mg / ml shows better solubility, so the crystalline polymorph of the invention can be As a preparation for oral administration, it has a good formulation efficiency when used for injections such as J. In addition, the polycrystalline polymorphs of the present invention exhibit excellent drug absorption properties at i = tola. However, the r-shaped crystal can be obtained by making 2- [4_ [2-[[((ls, 2R) —2-hydroxy-2) (j-hydroxyphenyl) -bumethylethyl] amino] ethyl] phenoxy It can be produced by dissolving in acetic acid in sodium hydroxide water> valley, neutralizing it with hydrochloric acid under ice-cooling, filtering out the precipitated crystals, and drying under reduced pressure at 400-600 ° C for several hours. And '5-shaped crystal can be obtained by making 2-[4-[2-[[(1S, 2R)-2-hydroxy, 2-(4- via phenyl)-1-amidinoethyl] amino] ethyl ] Phenoxy] acetic acid is dissolved in water and methanol (volume ratio of about 7: 3), concentrated under reduced pressure to avoid high temperature, and the precipitated crystals are collected by filtration, and dried under reduced pressure at 40-600x: 1.0. It can be manufactured in about 20 hours. [Best Mode for Carrying Out the Invention] The present invention will be described in detail using the following reference examples, examples, comparative examples, and test examples. The melting point of various crystalline polymorphs is measured using a differential thermal weight simultaneous measurement device (TG / DTA) Thermo plus TG8 120 from Ligacu Co., Ltd., and the temperature is measured at a temperature increase rate of 10 ° c / min, and the melting start temperature is extrapolated. The powder X-ray diffraction data of various crystalline polymorphs were measured using an X-ray diffraction device RINT1 400 from Ligacu Co., Ltd. and using CuK α-rays (1.541 A). Reference Example 1 2- "4- (2-hydroxyethyl) benzyl 1-ethyl acetate in a solution of 4- (2-hydroxyethyl) phenol (5 g) in acetone (45 ml),

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V. Description of the invention (5) Anhydrous potassium carbonate (6.5 g) was added at a temperature and stirred for 30 minutes. Ethyl bromoacetate (4.4 ml) was added dropwise to the mixture at an internal temperature of 40 to 45 ° C, and the mixture was stirred at 40 ° C for another 8 hours. The insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate) to obtain 2- [4- (2-hydroxyethyl) benzene. Oxy] ethyl acetate (5.8 g) 1H-NMR (CDC 13) δ ppm: 1.28 (3H, t, J = 7.1 Hz), 2.32 (lH, br) 2.76 (2H, t, J = 5.8 Hz ), 3.84 (2H, m), 4.24 (2H5q, J = 7.1Hz), 4.57 (2HJs), 6.88 (2H, d, J = 7.8Hz), 7.12 (2H, d, J: 7.8Hz ) Reference Example 2 [2 — [2-Bronze-Cycloethyl] Ethyl Acetate Acetate is intended for 2- [4- (2-hydroxyethyl) phenoxy] ethyl acetate (7.3 G) In a solution of ethyl acetate (2 2 liters), under a stream of nitrogen, triethylamine (5.9 ml) was added at room temperature and stirred. To this mixture, oxanesulfonic acid chloride (2.8 ml) was added dropwise at an internal temperature of 0 to 15 ° C, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the aqueous layer was separated. After the aqueous layer was extracted with ethyl acetate, the organic layers were combined, washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sulfuric acid. After the solvent was distilled off under reduced pressure, ethyl acetate (8.6 ml) and 2-propanol (23 ml) were added to the residue, and they were dissolved by heating. After cooling to room temperature, the precipitated crystals were collected by filtration to obtain 2- [4- (2-Methanesulfonyloxyethyl) phenoxy] ethyl acetate (7.2 g). M-NMR (CDC13) (5 ppm: 1.29 (3H, t, J = 7.1 Hz), 2.84 (3H, s) 2.99 (2H, t, J = 6.9 Hz), 4. · 26 (2H, q, J = 7.1 Hz), 4.37 (2H, t, J = 6.9Hz), 4.60 (2H, s),

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V. Description of the invention (6) 6.87 (2H, d, J = 8.7Hz), 7.15 (2H, d, J = 8.7Hz) Reference example 3 i- [4- 「2-「 「(1S, 2R) -2 Dihydroxy-2- (4-hydroxyphenylamino 1ethyl1benzyloxy] acetate and (1R, 2S) -2-amino-1- (4-hydroxyphenyl) propane Burnt-1-ol (8 · 8g), 2-[4-((2-Methylburntite yellow donkeyoxyethyl) phenoxy] acetic acid ethyl acetate (ΐ5.9g), 1

Isopropyl> 9 females (11 ¾ liters) and Ν, Ν- < -methyl ethyl amine (61 ¾ liters) were mixed under air flow at 7 5 C for 3.5 hours. The reaction mixture was cooled to a chamber, and after adding a mixed solution of ethyl acetate / benzene (9/1) and water, the aqueous layer was separated and the mixed solution of ethyl acetate / benzene (9/1) was added. Extract the aqueous layer. The organic layers were combined, washed with water and 18% brine, and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. After adding ethyl acetate (14 ml) and ethanol (92 ml) to the residue, a 16% phosphoric acid-ethanol solution (32 g) was added dropwise at room temperature with stirring, and the precipitated crystals were filtered to obtain 2- [4- [2-[[(1S, 2R)-2 -Ethyl-2- (4-lightphenyl) -1-amidinoethyl] amino] ethyl] phenoxy] ethyl acetate phosphoric acid Salt (1 2 · 4 g). 1H-NMR (DMSO-d6) δ ppm:

0.89 (3H, d, J = 6.6Hz), 1.23 (3H, t, J = 7.1Hz), 2.80-3. 15 (5H, m), 4.16 (2H, q, J = 7.1Hz) , 4.73 (2H, s), 4.92 (1H, br, s), 6. 71 (2H, d, J = 8. 6Hz), 6. 85 (2H, d, J = 8. 6Hz), 7. 13 (2H, d, J = 8.6 Hz), 7.16 (2H, d, J = 8.6 Hz), 7.92 (4H, br) Example 1 2-[4- 「2-「 「(lS, 2in-2_ hydroxy- 2- (4-Hydroxymolyl) -1-fluorenylamino 1 ethyl 1 cerium 1 acetic acid (α-shaped crystal)

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V. Description of the invention (7) In 2- [4- [2-[[(15,21〇-2-hydroxy-2- (4-hydroxyphenyl) -1_methylethyl] amino] ethyl ] Phenoxy] acetic acid diacetate (62 g), 2 mol / liter sodium hydroxide aqueous solution (393 ml) was added, and the inner temperature was heated to 40 ° C under stirring to dissolve .Drop 4 mol / litre salicylic acid salicylic acid solution (115 liters) at an internal temperature of 40 ~ 46 ° c, and stir at room temperature for one night, and then 'take out the precipitated crystals' and wash them with water' White crystals were obtained. The obtained crystals were suspended in a mixed solution of water / methanol (1/8) (200 ml), and suspended in the state of 'reflux for 30 minutes, and then cooled to room temperature. After filtering the crystals And dried under reduced pressure at 4 ° to 4 ° 5 ° C for 3 hours to obtain 2- [4- [2-[[(1S, 2R) -2 -Cyclo-2-(4-hydroxyphenyl) -1- Fluorenylethyl] amino] ethyl] phenoxy] acetic acid (α-shaped crystal) (50 · 0 g). The powder X-ray diffraction pattern of this crystalline polymorph (α-shaped crystal) is as follows It is shown in Figure 1. Melting point: 235 · 1 ° C (decomposition) 1H-NMR (DMSO-d6) δ ppm: 0.9K3H, d, J = 6. 6Hz), 2. 5 5-2. 75 (2H , m) 2. 9 0-3. 0 5 (2H, m), 3.15-3.25 (lH, ra), 4.25-4.40 (2H, m), 5.00-5.10 (lH, m), 6. 6 5-6. 80 (4H, m), 6 91 (2H, d, J = 8. 6Hz), 7. 13 (2H, d, J = 8.6Hz), 9.40 (1H, br) Specific rotation: [a] D25 = -10 · 〇. (C = l · 〇〇, 1 mole / liter hydrochloric acid) Comparative Example 1 2- [i- [2- [[(1S, 2R) -2 -Hydroxy-2- (4-hydroxybenzyl)-:- Methylethyl J Amino] ethyl] phenoxy 1 acetic acid (γ-shaped crystal) will be 2-[4-[2-[[(lS, 2R)-2-acetyl-2-(4- benzene Group) -bumethylethyl] amino] ethyl] phenoxy] acetic acid (a crystal) (1.4 g) at 1 mole /

89100860.ptd Page 13 1223647 V. Description of the invention (8) Dissolve in a liter of sodium hydroxide aqueous solution (20 ml) and water (125 ml), and add 1 mol / L hydrochloric acid (20) under ice-cold stirring. Ml). After stirring under ice cooling for 30 minutes, the precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure at 50 ° C for 3 hours to obtain 2- [4- [2-[[(1S, 2R) -2-hydroxy-2-( 4-Hydroxyphenyl) -oxenylethyl] amino] ethyl] phenoxy] acetic acid (y-shaped crystals) (0.78 g). The powder X-ray diffraction pattern of this crystalline polymorph (r-shaped crystal) is shown in Figure 2 below. Melting point: 189 · 8 ° C (decomposed)

2-[[(lS, 2R)-2- # yl-2- (4-hydroxybenzyl) -1-methylethyl] feyl] ethyl] benzyl 1acetic acid (5-form crystals) will be 2 -[4-[2-[[(1S, 2R) -2 -hydroxy-2-(4-hydroxyphenyl)-; 1 monomethylethyl] amino] ethyl] phenoxy] acetic acid (α Shape crystal) (2.0 g) was dissolved in a mixture of methanol (30 ml) and water (70 ml), and then cooled to room μ. After the insoluble matter was filtered off, the filtrate was concentrated under reduced pressure and left at room temperature for 30 minutes. The precipitated crystals were collected by filtration, and dried under reduced pressure at 40 ° C for 8 hours to obtain 2- [4- [2-[[(is, 2R) -2 -hydroxy-2-(4-hydroxyphenyl) monomethyl] Ethyl] amino] ethyl] phenoxy] acetic acid (5-form crystals) (8 g). Yet

The powder X-ray diffraction pattern of the crystalline polymorph (5-shaped crystal) is shown in Figure 3 below. Melting point: 236.3 ° C (decomposition) Test example 1 Hall stimulating effect Take out the uterus of SD pregnant rats (the 21st day of pregnancy) and avoid the placenta

1223647 V. Description of the invention (9) Part ′ is a specimen with a width of about 5mm and a length of about 5mm in the longitudinal muscle direction, and the experiment is performed according to the M agnus method. The specimen was suspended at 37 t and passed into a Locke-Ringer solution containing a mixed gas of 95% 02 and 5% C02, and a weight of 1 g was added. The isometric property is derived through a tension transducer, and the uterine movement is recorded automatically with Rectigraph. 2 ~ [4 — [2 _ [[(ls, 2R) -2—Hydroxy-2 — (4-Hydroxy, phenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid is Accumulate 5 minutes into Magnus tube. The drug evaluation of the compound is that the sum of the uterine contraction height for 5 minutes before adding the compound is regarded as 100%, and the sum of the uterine contraction height for 5 minutes after adding the compound in various waves is compared to 3. 1 x 1 0 8 (M) shows the drug concentration (EC5 () value) that inhibits the sum of 50% of the uterine contraction height. Test example 2

/ The urinary tube of male ferret (body weight 1100 ~ 1 400 g) was removed, and the connective tissue was removed, and then a specimen with a length of about 20 mm in the longitudinal axis was prepared and tested according to the Magnus method. The specimen was suspended at 37r and passed into a Krebs-Henseleit solution containing a mixed gas of 95% 02 and 5% C02, and a weight of 0.5 g was added. The isometric property is derived through a tension transducer, and the urinary tube is automatically moved with Rectigrap} ^ £. 2- [4-[2-[[(1S, 2R)-2-hydroxy-2-(4-hydroxyphenyl bu methyl ethyl] amino group >] ethyl] phenoxy] acetic acid every 3 minutes Cumulatively added to Magnus. The drug evaluation of this compound is to consider the sum of the urinary contraction height of 3 = minutes before the addition of this compound as 100%, and compare the 3 minutes after adding this compound at various multipliers. The sum of the urinary contraction height, at 丨 · 4 χ 1 〇_UM) shows the drug concentration (EC50) that inhibits the sum of 50% of the urinary contraction height.

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89100860.ptd Page 16 1223647 Brief description of the drawings [Simplified description of the drawings] Figure 1 is the 2- [4- [2-[[(lS, 2R) -2-hydroxy ~ 2 — (4—% # 基） -Bumethylethyl] amino] ethyl] phenoxy] acetic acid stalks… crystalline polymorphic I # (α-shaped crystal) powder X-ray diffraction pattern (using a monochromator), / And the axis is the diffraction intensity (Kcps), and the horizontal axis is 婢 ^ Shang, the vertical figure 2 is 2 1 [4— [2-[[(lS, 2R) 1 2-hydroxyl 2 ~ (4 2 Diagonal (2 θ). Polyethylethyl] amino] ethyl] phenoxy] acetic acid has many crystals, phenyl)-powder X-ray diffraction pattern (using a monochromator). Shang Kai body (7-shaped crystal), the radiation intensity (Kcps), the horizontal axis represents the diffraction angle (2 / 'the vertical axis represents the winding around Figure 3 is 2- [4-[2-[[(is, 2R) — 2 ~ Hydroxyethyl] Amine] Ethyl] phenoxy] acetic acid knot = ~ Hydroxybenzyl)-powder X-ray diffraction pattern (using a monochromator body (3-shaped crystal)) Intensity (KCPS), the horizontal axis represents the diffraction angle (2 ^ j, the vertical axis represents the winding 89100860.ptd $ 17 pages

Claims (1)

1223647 Six, patent application scope 1. A 2- [4- [2-[[(1S, 2R)-2-hydroxy-2- (4-hydroxyphenyl) -1-amidinoethyl] amino] ethyl Crystalline polymorphs of [phenoxy] acetic acid in powder X-ray diffraction patterns, in diffraction angles (2 < 9 ± 0 · 1 degree), at 10.8, 19.1, 19. 3, 19. 8., 20. 6 and 27.0 degrees show strong diffraction peaks. 89100860.ptd Page 18